This R24 Seed Program proposal concerns the development and analysis of novel chemical inhibitors of a key enzyme, ghrelin 0-acyltransferase (GOAT) that catalyzes a critical step in the biosynthesis of acyl ghrelin, a body mass and glucose regulatory hormone. The trend toward excessive body weight in the U.S. and global populations contributes to major morbidity in human health, not to mention spiraling medical costs. Likewise, the increasing prevalence of type II diabetes mellitus, predicted to reach 30% of the American population by 2050, is a tremendous epidemiologic concern. There is thus an urgent need for effective therapeutics that can combat obesity and diabetes. Synthetic compounds that block GOAT offer the potential for such metabolic therapies. The team leaders Philip Cole (PI, Johns Hopkins), Jef Boeke (Johns Hopkins), Matthias Tschop (Univ. Cincinnati), and Paul Pfluger (Univ. Cincinnati), experts in their respective fields, have recently joined forces to create an interdisciplinary, state-of the-art research program that integrates synthetic chemistry, enzymology, cellular pharmacology, pharmacokinetics, and mouse metabolic studies to develop novel GOAT inhibitors and evaluate their therapeutic potential. Building on significant preliminary data that show that designed peptide-based GOAT inhibitors work in vitro, in cells, and in mice to reduce acyl ghrelin, prevent weight gain, and improve glucose tolerance (B. Barnett et al. Science, Dec. 2010), this team will attempt to develop synthetic compounds with superior pharmacologic properties. These new compounds along with the prototype GOAT inhibitor GO-CoA-Tat will be used to dissect how the extent and mechanism of acyl/desacyl ghrelin changes affect the detailed energy and glucose/insulin profiles in wild-type and genetically altered mouse models on a range of diets. In summary, this program offers the exciting potential to generate next generation therapeutics that may safely help overcome the increasing public health challenges of obesity and diabetes. PUBLIC HEALTH RELEVANCE: This proposal could generate lead agents for the treatment of diabetes and obesity.